Interaction of bicyclo-octane analogs of amantadine with ionic channels of the nicotinic acetylcholine receptor and electrically excitable membrane.

A series of bicyclo-octane analogs of amantadine was investigated for their actions on ionic channels of electrically excitable membrane and of nicotinic acetylcholine receptors in frog sartorius muscles. Amantadine and three of its amine-substituted bicyclo-octane analogs (ID 11, 33 and 36) blocked neuromuscular transmission in a concentration-dependent manner. The dipropylaminomethyl analog (ID 36) also potentiated the directly elicited twitch concurrent with a prolongation of the directly elicited action potential; there was no block of delayed rectification. The peak amplitude of the end-plate current at -90 mV was reduced in a nearly equipotent manner by amantadine and ID 11, 33 and 36, but these three analogs were more potent than amantadine in shortening the time constant of end-plate current decay. The pattern of nonlinearity in the current/voltage relationship and area of negative slope conductance coupled with the depression and shortening of the end-plate current suggest that these analogs block neuromuscular transmission by interacting with the ionic channel of the acetylcholine receptor. Because carboxy-substituted analogs were ineffective and amine-substituted ones were effective, it appears that the site(s) which controls the opening and closing of the ionic channel require(s) a drug to penetrate a lipid barrier to a hydrophilic site in the membrane.